title: Therapeutic equivalence and pharmacokinetics of generic tacrolimus formulation in de novo kidney transplant patients.
abstract: BACKGROUND
  There is a growing concern about the therapeutic equivalence of the generic tacrolimus formulation (GEN Tacrolimus) to the reference tacrolimus (REF Tacrolimus) in solid organ transplantation.
  
  
  METHODS
  A prospective, randomized study of 126 de novo renal transplant patients was conducted to compare the efficacy, safety and pharmacokinetic (PK) profiles between GEN tacrolimus (n = 63) and REF tacrolimus (n = 63). The PK of tacrolimus was evaluated on Day 10 and 6 months under steady-state condition. Crossover study was carried out in 66 patients at 6 months.
  
  
  RESULTS
  On Day 10, 117 patients completed PK profiles (54 GEN tacrolimus and 63 REF tacrolimus) and GEN tacrolimus showed comparable C(0) (9.8 ± 2.5 versus 9.7 ± 3.0 ng/mL, P = 0.80) but significantly higher dose-normalized C(max) (309.1 ± 191.9 versus 192.5 ± 95.2 ng/mL/mg/kg, P < 0.001). The dose-normalized AUC(0-12) tended to be higher in the GEN tacrolimus than in the REF tacrolimus group (1513.4 ± 935.4 versus 1262.5 ± 593.5 ng.h/mL/mg/kg, P = 0.084). Because of this early and high C(max) with a rapid decline in GEN tacrolimus concentration, the trough concentration was maintained lower than that of REF tacrolimus. At 6 months, GEN tacrolimus showed equivalent dose-normalized AUC(0-12) (1882.2 ± 935.6 versus 1718.1 ± 946.3 ng.h/mL/mg/kg, P = 0.429) but still higher dose-normalized C(max) (346.3 ± 184.4 versus 273.2 ± 148.9 ng/mL/mg/kg, P = 0.056), despite a reduced trough concentration (5.7 ± 1.6 versus 6.9 ± 2.2 ng/mL, P = 0.004). PK profiles evaluated at 9 months showed that generic substitution also resulted in an 'early and high C(max)'. Efficacy and safety data were comparable over the 9-month study period.
  
  
  CONCLUSIONS
  Therapeutic equivalence and the PK of GEN tacrolimus should be evaluated in patients undergoing de novo renal transplantation.
authors.affiliation: Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Sang-Il
authors.initials: SI
authors.lastname: Min
authors.forename: Jongwon
authors.initials: J
authors.lastname: Ha
authors.forename: Yon Su
authors.initials: YS
authors.lastname: Kim
authors.forename: Sang Hyun
authors.initials: SH
authors.lastname: Ahn
authors.forename: Taejin
authors.initials: T
authors.lastname: Park
authors.forename: Dae Do
authors.initials: DD
authors.lastname: Park
authors.forename: Suh Min
authors.initials: SM
authors.lastname: Kim
authors.forename: Seung-Kee
authors.initials: SK
authors.lastname: Min
authors.forename: Hyejin
authors.initials: H
authors.lastname: Hong
authors.forename: Curie
authors.initials: C
authors.lastname: Ahn
authors.forename: Sang Joon
authors.initials: SJ
authors.lastname: Kim
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D018592:Cross-Over Studies; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D007674:Kidney Diseases / Q000628:therapy*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D016559:Tacrolimus / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D016559:Tacrolimus
keywords: generic tacrolimus formulation; interchangeability; renal transplantation; therapeutic drug monitoring